title: TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism.
abstract: The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions -124 and -146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.forename: Ismail
authors.initials: I
authors.lastname: Hosen
authors.forename: Petra J
authors.initials: PJ
authors.lastname: de Verdier
authors.forename: Mahdi
authors.initials: M
authors.lastname: Fallah
authors.forename: Barbara
authors.initials: B
authors.lastname: Heidenreich
authors.forename: Charlotta
authors.initials: C
authors.lastname: Ryk
authors.forename: N Peter
authors.initials: NP
authors.lastname: Wiklund
authors.forename: Gunnar
authors.initials: G
authors.lastname: Steineck
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000369:Aged, 80 and over; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000706:statistics & numerical data; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D019098:Telomerase / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase
keywords: TERT mutations; cancer genetics; noncoding mutations; reporter assays; transcription factors